Artemether Activation of AMPK/GSK3<i>β</i>(ser9)/Nrf2 Signaling Confers Neuroprotection towards <i>β-</i>Amyloid-Induced Neurotoxicity in 3xTg Alzheimer’s Mouse Model

Abstract

Alzheimer's disease is a severe neurodegenerative disease. Multiple factors involving neurofibrillary tangles and amyloid-<i>β</i> plaques lead to the progression of the AD, generated by aggregated hyperphosphorylated Tau protein. Inflammation, mitochondrial dysfunction, and oxidative stress play a significant role in the progression of AD. It has been therefore suggested that the multifactorial nature of AD pathogenesis requires the design of antioxidant drugs with a broad spectrum of neuroprotective activities. For this reason, the use of natural products, characterized by multiple pharmacological properties is advantageous as AD-modifying drugs over the single-targeted chemicals. Artemether, a peroxide sesquiterpenoid lipid-soluble compound, has been used in the clinic as an antimalarial drug. Also, it exhibits potent anti-inflammatory and antioxidant activities. Here, we report the neuroprotective effects of Artemether towards A<i>β</i>-induced neurotoxicity in neuronal cell cultures. A temporal correlation was found between Artemether neuroprotection towards A<i>β</i>-induced neurotoxicity and AMPK/GSK3<i>β</i> phosphorylation activity and increased expression of the activated Nrf2 signaling pathway. In 3xTg-AD mice, Artemether attenuated learning and memory deficits, inhibited cortical neuronal apoptosis and glial activation, inhibited oxidative stress through decrease of lipid peroxidation and increased expression of SOD, and reduced A<i>β</i> deposition and tau protein phosphorylation. Moreover, in 3xTg-AD mice, Artemether induced phosphorylation of the AMPK/GSK3<i>β</i> pathway which activated Nrf2, increasing the level of antioxidant protein HO-1. These activities probably produced the antioxidant and anti-inflammatory effects responsible for the neuroprotective effects of Artemether in the 3xTg-AD mouse model. These findings propose Artemether as a new drug for the treatment of AD disease.